Insulin is a naturally occurring hormone secreted by the beta cells of the islands of Langerhans in the pancreas in response to increased levels of glucose in the blood. The hormone acts to regulate the metabolism of glucose and the processes associated with the intermediary metabolism of fat, carbohydrates and proteins. Insulin lowers blood glucose levels and promotes transport and entry of glucose into muscle cells and other tissues. Due to the chemical nature of insulin molecules, the traditional route of insulin administration in diabetic patients, who require multiple daily doses of insulin, is intradermal or subdermal injection.
Prior art efforts to develop a non-injectable transdermal insulin delivery system for the treatment of diabetes have not been successful to date. While insulin can be systemically delivered to a patient by the topical application of an insulin-containing vehicle, the systemic blood levels of insulin that are achievable using this delivery method have proven to be generally inadequate for meeting the demands of the diabetic patient.
Various methods have been developed for enhancing the transdermal delivery of insulin including improved passive diffusion carriers for increasing the permeability of the epidermis, sonophoresis, iontophoresis and ionosonic transport. Passive diffusion through the outer layer of skin has been used successfully for the delivery of low molecular weight lipophilic drugs such as scopolamine, estradiol and nitroglycerine, but has been largely unsuccessful for the transdermal delivery of hydrophilic peptides such as insulin due to the low skin permeability of such peptides. Thus, mechanical vibrational energy and/or iontophoresis are employed to increase skin permeability and facilitate transdermal insulin delivery. Sibalis et al., in U.S. Pat. No. 4,940,456, teaches an apparatus and method for the iontophoretically mediated transdermal delivery of insulin. Henley, in U.S. Pat. Nos. 5,667,487 and 5,658,247 discloses an ionosonic apparatus suitable for the ultrasonic-iontophoretically mediated transport of therapeutic agents across the skin. Insulin has a tendency to form dimers and hexamers in pharmacological compositions, which are considered to be too large for transdermal delivery. Brange, in U.S. Pat. No. 5,597,796, suggests chemically modifying insulin to produce insulin analogs that resist intermolecular association and enable improved iontophoretic delivery. Jang et al., in U.S. Pat. No. 5,681,580, discloses a patch containing insulin formulated in a gel for the iontophoretically driven transdermal delivery of insulin. Notwithstanding the advances in methods for the transdermal delivery of insulin described above, the transdermal delivery of insulin in a quantity sufficient to attain a therapeutic level in the blood of diabetic patients has heretofore not been possible.
Clinical use of transdermal drug delivery has been limited because very few drugs are able, at least by passive diffusion alone, to penetrate the skin at a sufficient rate to produce a useful systemic drug concentration in the patient. The outer layer of the skin, the stratum corneum, is a major barrier to diffusion of low and especially high molecular weight drugs across the skin to the bloodstream. One drug for which an effective transdermal delivery system has long been sought is insulin, a therapeutic agent useful in the control of both Type I (juvenile onset) and Type II (adult onset) diabetes. Insulin, unfortunately, constitutes an example of molecules which do not readily diffuse through the stratum corneum at a therapeutically useful rate.
While there have been attempts in the prior art to develop transdermal “patches” which contain a particular amount of insulin, which may be transferred at a particular rate, these patches have numerous limitations. One specific limitation is that insulin users must often gauge their requirements relative to physical activity and ingestion of carbohydrates. Additionally, there are different types of insulin, e.g. long-acting and short-acting, and the patient must develop skill in blending both the type and quantity of insulin in order to adequately control their blood sugar levels. The use of multiple patches having variable dosage strengths and insulin response characteristics thus becomes problematic.
Thus there remains a longfelt need for a dermal delivery system for insulin in a convenient format, e.g. a gel or cream, which can be formulated with insulin compounds having varied release characteristics, and whereby the dosage could be determined as a function of the volume applied.